Atherosclerosis and its devastating clinical complications---arterial thrombosis, ischemia and infarction of the heart, brain and other vital organs, ruptured aortic aneurysms and peripheral vascular insufficiency---continue to account for the majority of the morbidity and mortality in the adult populations of industrialized nations. Despite major advances in our understanding of lipid metabolism and its role in promoting atheroma formation, much still remains to be learned about the pathobiology of atherosclerosis, in particular, how systemic risk factors such as hypercholesterolemia contribute to the progressive narrowing/remodeling, scarring/calcification, and lipid accumulation found at sites of atherosclerotic plaque formation. The primary focus of this new SCOR program will be atherogenesis, the pathogenetic sequence of events occurring within the arterial wall that leads to clinical disease. Our goal is to define the cellular and molecular mechanisms involved in certain critical transitions in the natural history of the atherosclerotic plaque, which underly its anatomical localization and temporal progression to an unstable/vulnerable stage predisposing to intravascular thrombosis. Project Aims include: (1) the discovery of endothelial genes induced by hemodynamic forces that contribute to localized lesion initiation; (2) testing in vivo the roles of matrix degrading proteinases, and pro-and anati-inflammatory cytokines, on aspects of arterial structure related to plaque stability; (3) exploring the mechanisms of recruitment of T-lymphocytes and their function(s) in lesion progression/regression; (4) defining the role of the NF- kappaB/IkappaB transcription factor system in the regulation of expression of atherosclerosis-related genes in the vascular wall; (5) applying the emerging technologies of nuclear magnetic resonance imaging and intravascular ultrasound, in animal models and human subjects, to study the mechanisms by which lipid-lowering interventions (dietary, pharmacologic) effect plaque structure and stability. An interdisciplinary team of basic investigators and clinician-scientists, with expertise in vascular biology, cardiovascular pathology and medicine, and biomechanical engineering, has been assembled in a supportive institutional environment. These studies should yield new insights into the pathogenesis and effective therapeutic interventions for atherosclerotic cardiovascular disease.